CA2535313C - Derives de purine servant a inhiber la replication du vih - Google Patents
Derives de purine servant a inhiber la replication du vih Download PDFInfo
- Publication number
- CA2535313C CA2535313C CA2535313A CA2535313A CA2535313C CA 2535313 C CA2535313 C CA 2535313C CA 2535313 A CA2535313 A CA 2535313A CA 2535313 A CA2535313 A CA 2535313A CA 2535313 C CA2535313 C CA 2535313C
- Authority
- CA
- Canada
- Prior art keywords
- 6alkyl
- aminocarbonyl
- cyano
- formula
- 4alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- 230000010076 replication Effects 0.000 title description 7
- 230000002401 inhibitory effect Effects 0.000 title description 6
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 title description 5
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 241
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 150000001204 N-oxides Chemical class 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 19
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 208000031886 HIV Infections Diseases 0.000 claims abstract description 16
- 208000037357 HIV infectious disease Diseases 0.000 claims abstract description 12
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 230000002265 prevention Effects 0.000 claims abstract description 7
- -1 cyano, aminocarbonyl Chemical group 0.000 claims description 211
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 149
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 144
- 125000001424 substituent group Chemical group 0.000 claims description 110
- 229920006395 saturated elastomer Polymers 0.000 claims description 95
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 92
- 125000002619 bicyclic group Chemical group 0.000 claims description 80
- 125000002950 monocyclic group Chemical group 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 125000003118 aryl group Chemical group 0.000 claims description 62
- 239000001257 hydrogen Substances 0.000 claims description 51
- 238000002360 preparation method Methods 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
- 239000002904 solvent Substances 0.000 claims description 48
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 47
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 39
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 18
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 10
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 9
- 230000000798 anti-retroviral effect Effects 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 101100240519 Caenorhabditis elegans nhr-13 gene Chemical group 0.000 claims description 7
- 239000003446 ligand Substances 0.000 claims description 7
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 7
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 17
- 125000003277 amino group Chemical group 0.000 claims 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 7
- 150000002431 hydrogen Chemical group 0.000 claims 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims 2
- 125000000815 N-oxide group Chemical group 0.000 claims 1
- 229910019213 POCl3 Inorganic materials 0.000 claims 1
- 150000001412 amines Chemical group 0.000 abstract description 24
- 239000000543 intermediate Substances 0.000 description 179
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 100
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 239000010410 layer Substances 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 53
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 125000005843 halogen group Chemical group 0.000 description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 31
- 239000007832 Na2SO4 Substances 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 30
- 150000003254 radicals Chemical group 0.000 description 30
- 229910052938 sodium sulfate Inorganic materials 0.000 description 30
- 235000011152 sodium sulphate Nutrition 0.000 description 30
- 238000000034 method Methods 0.000 description 27
- 235000017557 sodium bicarbonate Nutrition 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- 239000011780 sodium chloride Substances 0.000 description 25
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 241000725303 Human immunodeficiency virus Species 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- 229920000858 Cyclodextrin Polymers 0.000 description 22
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 229910001868 water Inorganic materials 0.000 description 18
- 125000004122 cyclic group Chemical group 0.000 description 17
- 239000003480 eluent Substances 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 14
- 238000012746 preparative thin layer chromatography Methods 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 12
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 12
- 239000007962 solid dispersion Substances 0.000 description 12
- 229920003169 water-soluble polymer Polymers 0.000 description 12
- 101150041968 CDC13 gene Proteins 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- 229910000024 caesium carbonate Inorganic materials 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 229940097362 cyclodextrins Drugs 0.000 description 11
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 11
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000006104 solid solution Substances 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 5
- 206010001513 AIDS related complex Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 208000036142 Viral infection Diseases 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 5
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 229960005486 vaccine Drugs 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- 208000030507 AIDS Diseases 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102100034343 Integrase Human genes 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 108091006629 SLC13A2 Proteins 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000004811 liquid chromatography Methods 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000000750 progressive effect Effects 0.000 description 4
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 4
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 4
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 3
- CTTUQCIBNSCQRH-UHFFFAOYSA-N 2,3,4-trimethylpentan-3-amine Chemical compound CC(C)C(C)(N)C(C)C CTTUQCIBNSCQRH-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 3
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- BJXYHBKEQFQVES-NWDGAFQWSA-N enpatoran Chemical compound N[C@H]1CN(C[C@H](C1)C(F)(F)F)C1=C2C=CC=NC2=C(C=C1)C#N BJXYHBKEQFQVES-NWDGAFQWSA-N 0.000 description 3
- 239000002024 ethyl acetate extract Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 150000003212 purines Chemical class 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- 241001430294 unidentified retrovirus Species 0.000 description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Virology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- AIDS & HIV (AREA)
- Tropical Medicine & Parasitology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
L'invention concerne l'utilisation d'un composé de formule (I) pour produire un médicament servant à prévenir ou traiter une infection par le VIH. Selon l'invention : le composé de formule (I) est un composé de formule (I) ou un <I>N</I>-oxyde, un sel d'addition pharmaceutiquement acceptable, une amine quaternaire ou une forme stéréo-isomère de celui-ci ; A et B représentent respectivement un radical de formule (a) ou (b), et ; -C-D- désigne un radical bivalent de formule -N=CH-NR?17¿- (c-1) ou -NR?17¿-CH=N- (c-2) ; à condition que lorsque A désigne un radical de formule (a), B représente un radical de formule (b), et que lorsque A désigne un radical de formule (b), B représente un radical de formule (a).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EPPCT/EP03/50659 | 2003-09-25 | ||
| EP0350659 | 2003-09-25 | ||
| PCT/EP2004/052262 WO2005028479A2 (fr) | 2003-09-25 | 2004-09-21 | Derives de purine servant a inhiber la replication du vih |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2535313A1 CA2535313A1 (fr) | 2005-03-31 |
| CA2535313C true CA2535313C (fr) | 2012-07-17 |
Family
ID=34354400
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2535313A Expired - Fee Related CA2535313C (fr) | 2003-09-25 | 2004-09-21 | Derives de purine servant a inhiber la replication du vih |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US8026245B2 (fr) |
| EP (1) | EP1668011B1 (fr) |
| JP (1) | JP5506751B2 (fr) |
| KR (1) | KR20060121878A (fr) |
| CN (1) | CN100475815C (fr) |
| AP (1) | AP2006003517A0 (fr) |
| AT (1) | ATE500254T1 (fr) |
| AU (1) | AU2004274185B2 (fr) |
| BR (1) | BRPI0414791A (fr) |
| CA (1) | CA2535313C (fr) |
| DE (1) | DE602004031641D1 (fr) |
| EA (1) | EA009734B1 (fr) |
| ES (1) | ES2361835T3 (fr) |
| IL (1) | IL174467A0 (fr) |
| MX (1) | MXPA06002069A (fr) |
| NO (1) | NO20061788L (fr) |
| TW (1) | TW200518758A (fr) |
| WO (1) | WO2005028479A2 (fr) |
| ZA (1) | ZA200602440B (fr) |
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| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| HRP20050089B1 (hr) | 2002-07-29 | 2015-06-19 | Rigel Pharmaceuticals | Upotreba 2,4 pirimidindiaminskog spoja za proizvodnju lijeka za lijeäśenje ili sprjeäśavanje autoimunosne bolesti |
| WO2005012294A1 (fr) | 2003-07-30 | 2005-02-10 | Rigel Pharmaceuticals, Inc. | Composes 2,4-pyrimidinediamine a utiliser dans le traitement ou la prevention de maladies auto-immunes |
| EP1720877A4 (fr) * | 2004-03-02 | 2009-11-04 | Neurogen Corp | Analogues des purines substitution aryle |
| DK2135608T3 (da) | 2004-08-25 | 2012-01-23 | Ardea Biosciences Inc | S-triazolyl-alfa-mercaptoacetanilider som inhibitorer for HIV-revers transkriptase |
| WO2007050087A1 (fr) | 2004-08-25 | 2007-05-03 | Ardea Biosciences, Inc. | Acides N[S(4-aryltriazol-3-yl)α-mercaptoacétyl]-p-aminobenzoïques EN TANT QU'INHIBITEURS DE TRANSCRIPTASE INVERSE DE VIH |
| MX2007003332A (es) | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores de estearoil-coa-desaturasa. |
| BRPI0515500A (pt) | 2004-09-20 | 2008-07-29 | Xenon Pharmaceuticals Inc | derivados piridazina para inibição de estearoil-coa-desaturase |
| AU2005286647A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
| MX2007003318A (es) | 2004-09-20 | 2007-05-18 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como agentes terapeuticos. |
| AU2005286728A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase |
| CN101084211A (zh) | 2004-09-20 | 2007-12-05 | 泽农医药公司 | 杂环衍生物及其作为治疗剂的用途 |
| BRPI0515482A (pt) | 2004-09-20 | 2008-07-22 | Xenon Pharmaceuticals Inc | derivados heterocìclicos e seus usos como agentes terapêuticos |
| AU2006230447A1 (en) | 2005-03-30 | 2006-10-05 | Conforma Therapeutics Corporation | Alkynyl pyrrolopyrimidines and related analogs as HSP90-inhibitors |
| AU2006244195B2 (en) | 2005-05-05 | 2012-03-15 | Ardea Biosciences, Inc. | Diaryl-purine, azapurines and -deazapurines as non-nucleoside reverse transcriptase inhibitors for treatment of HIV |
| WO2006136005A1 (fr) * | 2005-05-16 | 2006-12-28 | Prometic Biosciences Inc. | Derives de purine et utilisation de ceux-ci dans le traitement de maladies auto-immunes |
| CA2618646A1 (fr) | 2005-06-03 | 2007-11-15 | Xenon Pharmaceuticals Inc. | Derives aminothiazole utilises en tant qu'inhibiteurs de la stearoyle-coa desaturase humaine |
| BRPI0610876B8 (pt) | 2005-06-08 | 2021-05-25 | Rigel Pharmaceuticals Inc | composto, formulação farmacêutica, e métodos de inibir uma atividade de uma jak cinase, e de inibir uma cascata de transdução de sinal em que jak3 cinase desempenha um papel |
| US20070203161A1 (en) | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| ES2622493T3 (es) | 2006-02-24 | 2017-07-06 | Rigel Pharmaceuticals, Inc. | Composiciones y métodos para la inhibición de la ruta de JAK |
| EP2132211A4 (fr) * | 2006-11-09 | 2011-12-07 | Ardea Biosciences Inc | Composés hétérocycliques bicycliques 4-cyanophénylamino-substitués utilisés comme inhibiteurs du vih |
| AU2008210455A1 (en) | 2007-01-31 | 2008-08-07 | Vertex Pharmaceuticals Incorporated | 2-aminopyridine derivatives useful as kinase inhibitors |
| ME01294B (fr) | 2007-11-27 | 2013-06-20 | Ardea Biosciences Inc | Nouveaux composés et nouvelles compositions et leurs procédés d'utilisation |
| ES2389752T3 (es) | 2007-12-14 | 2012-10-31 | Ardea Biosciences, Inc. | Inhibidores de la transcriptasa inversa |
| US8569337B2 (en) | 2008-07-23 | 2013-10-29 | Vertex Pharmaceuticals Incorporated | Tri-cyclic pyrazolopyridine kinase inhibitors |
| ES2402087T3 (es) | 2008-07-23 | 2013-04-26 | Vertex Pharmaceuticals Incorporated | Inhibidores de la pirazolopiridina quinasa |
| AU2009274023A1 (en) | 2008-07-23 | 2010-01-28 | Vertex Pharmaceuticals Incorporated | Tri-cyclic pyrazolopyridine kinase inhibitors |
| CA2732765A1 (fr) | 2008-08-06 | 2010-02-11 | Vertex Pharmaceuticals Incorporated | Inhibiteurs d'aminopyridine kinase |
| CA2760705A1 (fr) | 2009-05-06 | 2010-11-11 | Vertex Pharmaceuticals Incorporated | Pyrazolopyridines |
| EP2499143B1 (fr) | 2009-11-12 | 2016-03-16 | F.Hoffmann-La Roche Ag | Composés des purines n7-substituées et des pyrazolopyrimidines, compositions et les procédés pour leur utilisation |
| JP5769733B2 (ja) | 2010-01-27 | 2015-08-26 | バーテックス ファーマシューティカルズ インコーポレイテッドVertex Pharmaceuticals Incorporated | ピラゾロピリジンキナーゼ阻害剤 |
| CA2787079A1 (fr) | 2010-01-27 | 2011-08-04 | Vertex Pharmaceuticals Incorporated | Inhibiteurs de la pyrazolopyrazine kinase |
| EP2582702A1 (fr) | 2010-01-27 | 2013-04-24 | Vertex Pharmaceuticals Incorporated | Inhibiteurs des kinases à base de pyrazolopyrimidine |
| WO2011103457A1 (fr) | 2010-02-18 | 2011-08-25 | Concert Pharmaceuticals Inc. | Dérivés de la pyrimidine |
| FR2962437B1 (fr) | 2010-07-06 | 2012-08-17 | Sanofi Aventis | Derives d'imidazopyridine, leur procede de preparation et leur application en therapeutique |
| FR2962438B1 (fr) | 2010-07-06 | 2012-08-17 | Sanofi Aventis | Derives d'indolizines, procedes de preparation et application en therapeutique |
| CN103570688B (zh) * | 2012-07-19 | 2016-06-08 | 中国科学院上海药物研究所 | 2,5-二氨甲基吡嗪类化合物、其药物组合物、制备方法和用途 |
| WO2015115673A1 (fr) | 2014-01-31 | 2015-08-06 | Ono Pharmaceutical Co., Ltd. | Composés d'imidazole condensés |
| EP3235799B1 (fr) | 2014-12-18 | 2022-02-23 | Nissan Chemical Corporation | Oxime et herbicide |
| EP3528816A4 (fr) * | 2016-10-21 | 2020-04-08 | Nimbus Lakshmi, Inc. | Inhibiteurs de tyk2 et leurs utilisations |
| US20210380540A1 (en) * | 2018-10-25 | 2021-12-09 | Minakem | Process for the preparation of rilpivirine |
| CN110526873B (zh) * | 2019-08-15 | 2022-09-16 | 复旦大学 | 氰乙烯基取代的苯并二芳基嘧啶类化合物及其制备方法和用途 |
| CN114805369B (zh) * | 2022-05-30 | 2023-05-16 | 自贡市第四人民医院(自贡市急救中心) | 一种2,6-二取代嘌呤类化合物及制备方法及应用 |
| KR20250101955A (ko) * | 2023-12-27 | 2025-07-04 | 주식회사 에이조스바이오 | 신규 퓨린계 화합물 및 이의 용도 |
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| US3459731A (en) | 1966-12-16 | 1969-08-05 | Corn Products Co | Cyclodextrin polyethers and their production |
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| EA002973B1 (ru) | 1998-03-27 | 2002-12-26 | Янссен Фармацевтика Н.В. | Производные пиримидина в качестве ингибиторов репликации вируса иммунодефицита человека |
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| GB9918035D0 (en) * | 1999-07-30 | 1999-09-29 | Novartis Ag | Organic compounds |
| IL150594A0 (en) | 2000-01-07 | 2003-02-12 | Ustav Ex Botan Adademie Ved Ce | Purine derivatives, process for their preparation and use |
| JO3429B1 (ar) | 2001-08-13 | 2019-10-20 | Janssen Pharmaceutica Nv | مشتقات برميدينات مثبطة فيروس الايدز |
| US6897307B2 (en) * | 2002-03-28 | 2005-05-24 | Novartis Ag | Process for preparing 2,6-diaminopurine derivatives |
| MXPA06001758A (es) * | 2003-08-15 | 2006-08-11 | Irm Llc | Anilino purinas sustituidas en la posicion 6 utiles como inhibidores de rtk. |
| AU2006244195B2 (en) * | 2005-05-05 | 2012-03-15 | Ardea Biosciences, Inc. | Diaryl-purine, azapurines and -deazapurines as non-nucleoside reverse transcriptase inhibitors for treatment of HIV |
-
2004
- 2004-09-21 CN CNB2004800278401A patent/CN100475815C/zh not_active Expired - Fee Related
- 2004-09-21 BR BRPI0414791-0A patent/BRPI0414791A/pt not_active Application Discontinuation
- 2004-09-21 MX MXPA06002069A patent/MXPA06002069A/es active IP Right Grant
- 2004-09-21 WO PCT/EP2004/052262 patent/WO2005028479A2/fr not_active Ceased
- 2004-09-21 US US10/573,364 patent/US8026245B2/en not_active Expired - Fee Related
- 2004-09-21 AT AT04766834T patent/ATE500254T1/de not_active IP Right Cessation
- 2004-09-21 AU AU2004274185A patent/AU2004274185B2/en not_active Ceased
- 2004-09-21 AP AP2006003517A patent/AP2006003517A0/xx unknown
- 2004-09-21 KR KR1020067005328A patent/KR20060121878A/ko not_active Withdrawn
- 2004-09-21 EP EP04766834A patent/EP1668011B1/fr not_active Expired - Lifetime
- 2004-09-21 DE DE602004031641T patent/DE602004031641D1/de not_active Expired - Lifetime
- 2004-09-21 ES ES04766834T patent/ES2361835T3/es not_active Expired - Lifetime
- 2004-09-21 EA EA200600648A patent/EA009734B1/ru not_active IP Right Cessation
- 2004-09-21 CA CA2535313A patent/CA2535313C/fr not_active Expired - Fee Related
- 2004-09-24 TW TW093128936A patent/TW200518758A/zh unknown
-
2006
- 2006-03-21 IL IL174467A patent/IL174467A0/en active IP Right Grant
- 2006-03-24 ZA ZA200602440A patent/ZA200602440B/en unknown
- 2006-04-24 NO NO20061788A patent/NO20061788L/no not_active Application Discontinuation
-
2011
- 2011-08-01 JP JP2011168572A patent/JP5506751B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA06002069A (es) | 2006-05-19 |
| JP2012006945A (ja) | 2012-01-12 |
| ZA200602440B (en) | 2007-09-26 |
| AU2004274185B2 (en) | 2009-12-10 |
| DE602004031641D1 (de) | 2011-04-14 |
| JP5506751B2 (ja) | 2014-05-28 |
| NO20061788L (no) | 2006-04-24 |
| EA009734B1 (ru) | 2008-02-28 |
| ES2361835T3 (es) | 2011-06-22 |
| CN1856496A (zh) | 2006-11-01 |
| EP1668011A2 (fr) | 2006-06-14 |
| CN100475815C (zh) | 2009-04-08 |
| US8026245B2 (en) | 2011-09-27 |
| KR20060121878A (ko) | 2006-11-29 |
| JP2007506707A (ja) | 2007-03-22 |
| AP2006003517A0 (en) | 2006-02-28 |
| US20060293330A1 (en) | 2006-12-28 |
| WO2005028479A3 (fr) | 2005-06-16 |
| AU2004274185A1 (en) | 2005-03-31 |
| ATE500254T1 (de) | 2011-03-15 |
| EA200600648A1 (ru) | 2006-08-25 |
| WO2005028479A2 (fr) | 2005-03-31 |
| EP1668011B1 (fr) | 2011-03-02 |
| JP4825672B2 (ja) | 2011-11-30 |
| TW200518758A (en) | 2005-06-16 |
| CA2535313A1 (fr) | 2005-03-31 |
| BRPI0414791A (pt) | 2006-11-21 |
| IL174467A0 (en) | 2006-08-01 |
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Legal Events
| Date | Code | Title | Description |
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| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20210921 |